Age‐dependent NMDA receptor function is regulated by the amyloid precursor protein

• Published in: Aging cell Vol. 22; no. 3
• Main Authors: Rajão‐saraiva, Joana, Dunot, Jade, Ribera, Aurore, Temido-Ferreira, Mariana, Coelho, Joana E, König, Svenja, Moreno, Sébastien, Enguita, Francisco J, Willem, Michael, Kins, Stefan, Marie, Hélène, Lopes, Luísa V, Pousinha, Paula A
• Format: Journal Article
• Language: English
• Published: Wiley Open Access 01.03.2023
• Subjects: Life Sciences; ifenprodil; CTFs; control short-hairpin RNA shRNA; nonsilencing sequence pGluN2B; shAPP; shCTR; NS1; PTB2 peptide; Postsynaptic density protein 95 PSEN1; PTB1-p; polyvinylidene fluoride ROI; N-methyl-D-aspartate receptors NS1; presenilin-1; nonsilencing sequence; triple conditional knockout; field excitatory postsynaptic potentials; β-secretase 1 BI; PVDF; amyloid beta; long-term depression LTP; excitatory postsynaptic currents; NMDAR; SEM; days in vitro EPSCs; PTB2 peptide PVDF; standard error of the mean; long-term potentiation; β-secretase 1 inhibitor Ca2; CTFβ; RT; CTFα; BI; PSEN1; PTB1 peptide; PTB2-p; β-secretase 1; control short-hairpin RNA; cTKO; ifenprodil IPTG; PTB1 peptide PTB2-p; microtubule-associated protein tau NMDAR; phosphorylated GluN2B PSD; postsynaptic density; EPSCs; APP C-terminal fragment β cTKO; excitatory postsynaptic currents fEPSPs; DIV; pGluN2B; Ca2; secreted APP α sAPPβ; region of interest; APP C-terminal fragment β; APP C-terminal fragment α; Postsynaptic density protein 95; Calcium CTFs; Ifen; fEPSPs; short-hairpin RNA against APP; Aβ; shRNA; region of interest RT; long-term potentiation MAPT; APP C-terminal fragments; PSD; long-term depression; weighted component; Isopropyl β-D-1-thiogalactopyranoside; β-secretase 1 inhibitor; ROI; short-hairpin RNA; sAPPα; Isopropyl β-D-1-thiogalactopyranoside LTD; BACE1; triple conditional knockout DIV; presenilin-1 PTB1-p; standard error of the mean shAPP; secreted APP α; secreted APP β; polyvinylidene fluoride; sAPPβ; days in vitro; MAPT; LTD; room temperature; field excitatory postsynaptic potentials Ifen; APP C-terminal fragments CTFα; Calcium; LTP; APP C-terminal fragment α CTFβ; secreted APP β SEM; postsynaptic density PSD-95; microtubule-associated protein tau; short-hairpin RNA τweighted; τweighted; amyloid beta BACE1; room temperature sAPPα; N-methyl-D-aspartate receptors; IPTG; short-hairpin RNA against APP shCTR; phosphorylated GluN2B; PSD-95
• ISSN: 1474-9718; 1474-9728
• DOI: 10.1111/acel.13778

Abstract N‐methyl‐D‐aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A and/or GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch‐clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B‐NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B‐NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic‐derived C‐terminal fragments, rather than APP full‐length, contribute to aberrant GluN2B‐NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain. Interfering with stability or production of the APP intracellular domain normalized the GluN2B‐NMDARs currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age‐related synaptic impairments.